ADAM17-triggered TNF signalling protects the ageing Drosophila retina from lipid droplet mediated degeneration

Animals have evolved multiple mechanisms to protect themselves from the cumulative effects of age-related cellular damage. Here we reveal an unexpected link between the TNF (tumour necrosis factor) inflammatory pathway, triggered by the metalloprotease ADAM17/TACE, and a lipid droplet (LD)-mediated mechanism of protecting retinal cells from age related degeneration. Loss of ADAM17, TNF and the TNF receptor Grindelwald in pigmented glial cells of the Drosophila retina leads to age related degeneration of both glia and neurons, preceded by an abnormal accumulation of glial LDs. We show that the glial LDs initially buffer the cells against damage caused by neuronally generated reactive oxygen species (ROS), but that in later life the LDs dissipate, leading to the release of toxic peroxidated lipids. Finally, we demonstrate the existence of a conserved pathway in human iPS-derived microglia-like cells, which are central players in neurodegeneration. Overall, we have discovered a pathway mediated by TNF signalling acting not as a trigger of inflammation, but as a cytoprotective factor in the retina.

Anti-TNF Therapy in Crohn’s Disease

Crohn’s disease (CD) accounts for a variety of clinical manifestations or phenotypes that stem from chronic inflammation in the gastrointestinal tract. Its worldwide incidence is increasing including younger or childhood-onset of disease. The natural history of Crohn’s disease is characterized by a remitting and relapsing course that progresses to complications and surgery in most patients. The goals of treatment are to achieve clinical and endoscopic remission, to avoid disease progression and minimise surgical resections. Medical treatment usually features antibiotics, corticosteroids, immunomodulators (thiopurines, methotrexate). Anti-TNF (tumour necrosis factor) therapy was approved for use in Crohn’s disease in 1998, and has changed the paradigm of treatment, leading to improved rates of response and remission in patients. There are significant considerations that need to be borne in mind, when treating patients including immunogenicity, safety profile and duration of treatment.

The long and winding TRAIL to weight loss

TRAIL [TNF (tumour necrosis factor)-related apoptosis-inducing ligand] is in clinical trials for the treatment of cancer. In the present issue of Clinical Science, Bernardi and co-workers report that the administration of TRAIL in mice fed on a high-fat diet resulted in reduced adiposity and improved metabolic responses to a glucose and insulin tolerance test compared with mice without TRAIL. The metabolic improvements were associated with a higher rate of apoptotic fat cells and with a reduction in the levels of pro-inflammatory cytokines. These results suggest that TRAIL could be an exciting new therapeutic for treating obesity, but further studies are required to determine its major mechanisms of action.

Palmitoylation of the TRAIL receptor DR4 confers an efficient TRAIL-induced cell death signalling

S-palmitoylation is a lipid modification that regulates membrane–protein association and influences protein trafficking, stability or aggregation, thus playing an important role in protein signalling. We previously demonstrated that the palmitoylation of Fas, one of the DD (death domain)-containing members of the TNFR [TNF (tumour necrosis factor) receptor] superfamily, is essential for the redistribution of this receptor into lipid rafts, an obligatory step for the death signal transmission. Here we investigate the requirement of protein palmitoylation in the activities of other DD-containing death receptors. We show that DR4 is palmitoylated, whereas DR5 and TNFR1 are not. Furthermore, DR4 palmitoylation is required for its raft localization and its ability to oligomerize, two essential features in TRAIL (TNF-related apoptosis-inducing ligand)-induced death signal transmission.

Host response to cytoadherence in Plasmodium falciparum

Cytoadherence of PRBCs (Plasmodium falciparum-infected red blood cells) to host endothelium has been associated with pathology in severe malaria, but, despite extensive information on the primary processes involved in the adhesive interactions, the mechanisms underlying the disease are poorly understood. Endothelial cells have the ability to mobilize immune and pro-adhesive responses when exposed to both PRBCs and TNF (tumour necrosis factor). In addition, there is also an up-regulation by PRBCs and TNF and a concurrent down-regulation of a range of genes involved in inflammation and cell death, by PRBCs and TNF. We propose that the balance between positive and negative regulation will contribute to endothelial pathology during malarial infection. Apposition of PRBCs has been shown by a number of groups to activate signalling pathways. This is dependent, at least in part, on the cytoadherence characteristics of the invading isolate, such that the avidity of the PRBC for the receptor on host endothelium is proportional to the level of activation of the signalling pathways. An understanding of the post-adhesive processes produced by cytoadherence may help us to understand the variable pathology seen in malaria and to design appropriate therapies to alleviate severe disease.

Tumour necrosis factor induces phosphorylation primarily of the nitric-oxide-responsive form of glyoxalase I

We have previously shown that TNF (tumour necrosis factor) induces phosphorylation of GLO1 (glyoxalase I), which is required for cell death in L929 cells. In the present paper, we show that the TNF-induced phosphorylation of GLO1 occurs primarily on the NO (nitric oxide)-responsive form of GLO1. In addition, analysis of several cysteine mutants of GLO1 indicated that Cys-138, in combination with either Cys-18 or Cys-19, is a crucial target residue for the NO-mediated modification of GLO1. Furthermore, the NO-donor GSNO (S-nitrosogluthathione) induces NO-mediated modification of GLO1 and enhances the TNF-induced phosphorylation of this NO-responsive form. GSNO also strongly promotes TNF-induced cell death. By the use of pharmacological inhibition of iNOS (inducible NO synthase) and overexpression of mutants of GLO1 that are deficient for the NO-mediated modification, we have shown that the NO-mediated modification of GLO1 is not a requirement for TNF-induced phosphorylation or TNF-induced cell death respectively. In summary, these data suggest that the TNF-induced phosphorylation of GLO1 is the dominant factor for cell death.